NO145308B - PROCEDURE FOR THE PREPARATION OF AURANOFINE - Google Patents
PROCEDURE FOR THE PREPARATION OF AURANOFINE Download PDFInfo
- Publication number
- NO145308B NO145308B NO782242A NO782242A NO145308B NO 145308 B NO145308 B NO 145308B NO 782242 A NO782242 A NO 782242A NO 782242 A NO782242 A NO 782242A NO 145308 B NO145308 B NO 145308B
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- Prior art keywords
- acetyl
- methanol
- glycopyranose
- thio
- tetra
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- 238000000034 method Methods 0.000 title claims description 8
- IRPYFWIZKIOHQN-XTZHGVARSA-N gold;[(2r,3r,4s,5r,6s)-3,4,5-triacetyloxy-6-sulfanyloxan-2-yl]methyl acetate;triethylphosphane Chemical compound [Au].CC[PH+](CC)CC.CC(=O)OC[C@H]1O[C@@H]([S-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O IRPYFWIZKIOHQN-XTZHGVARSA-N 0.000 title 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 claims description 12
- 229960005207 auranofin Drugs 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- -1 carbon ion Chemical class 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical group [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- ASGJEMPQQVNTGO-UHFFFAOYSA-N benzene chloroform Chemical compound C(Cl)(Cl)Cl.C1=CC=CC=C1.C1=CC=CC=C1 ASGJEMPQQVNTGO-UHFFFAOYSA-N 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- RQNLZJKKRCHAAV-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-2-tritylbenzene Chemical compound C=1C=CC=CC=1C(C=1C(=CC=CC=1)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 RQNLZJKKRCHAAV-UHFFFAOYSA-N 0.000 description 1
- XQJCFOOAJAADSR-UHFFFAOYSA-N 1-bromo-4-[bromo(phenyl)methyl]benzene Chemical compound C=1C=C(Br)C=CC=1C(Br)C1=CC=CC=C1 XQJCFOOAJAADSR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical compound ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229940124346 antiarthritic agent Drugs 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- SYBBXLKWGHAVHP-UHFFFAOYSA-M chlorogold;triethylphosphane Chemical compound [Cl-].[Au+].CCP(CC)CC SYBBXLKWGHAVHP-UHFFFAOYSA-M 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- CLEUDPVZNLAYBR-UHFFFAOYSA-K gold(3+);triethylphosphane;trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Au+3].CCP(CC)CC.CCP(CC)CC CLEUDPVZNLAYBR-UHFFFAOYSA-K 0.000 description 1
- XGELIJUZAOYNCA-UHFFFAOYSA-N gold;phosphane Chemical group P.[Au] XGELIJUZAOYNCA-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- JELHWNHHIOMFRD-UHFFFAOYSA-K tribromogold;triethylphosphane Chemical compound [Br-].[Br-].[Br-].[Au+3].CCP(CC)CC JELHWNHHIOMFRD-UHFFFAOYSA-K 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cosmetics (AREA)
Description
Foreliggende oppfinnelse vedrører en hittil ukjent kjemisk fremgangsmåte for fremstilling av auranofin og dens beslektede forbindelser, som anvender som hovedutgangsmateriale en 2,3,-4,6-tetra-0-acetylglykopyranosylthioeter eller thioester, The present invention relates to a hitherto unknown chemical process for the production of auranofin and its related compounds, which uses as the main starting material a 2,3,-4,6-tetra-0-acetylglycopyranosylthioether or thioester,
hvis aglykondel (R) er en lett tilgjengelig avgangsgruppe som et stabilisert karbonion eller en lett tilgjengelig fortrengelig gruppe som en acylgruppe. Dette eter- whose aglycone moiety (R) is a readily available leaving group such as a stabilized carbon ion or a readily available displaceable group such as an acyl group. This ether-
eller esterutgangsmaterialet fås til å reagere med en reak-sjonsdyktig tertiær fosfingullester eller sulfid. or the ester starting material is made to react with a reactive tertiary phosphine gold ester or sulphide.
Auranofin er et oralt aktivt antiartritisk middel, som er nyttig for mennesker [J. Med. Chem. 15 1095 (1972), U.S. pat-ent nr.. 3.635 .945]. Ifølge disse litteratursteder fremstilles auranofin ved reaksjon av et alkalimetallsalt av en 1-thio-B-D-glykopyranose med et trialkylfosfingullhalogenid. Den foreliggende oppfinnelse menes å være helt forskjellig fra disse tidligere kjente fremgangsmåter. Auranofin is an orally active antiarthritic agent useful in humans [J. With. Chem. 15 1095 (1972), U.S. patent no. 3,635,945]. According to these literature sources, auranofin is produced by reaction of an alkali metal salt of a 1-thio-B-D-glycopyranose with a trialkylphosphine gold halide. The present invention is believed to be completely different from these previously known methods.
Fremgangsmåten ifølge oppfinnelsen illustreres av følgende: The method according to the invention is illustrated by the following:
hvor R er trifenylmetyl, lavere alkanoyl eller Ag hvor n er 1 eller 2, X er klor, brom, eller jod eller, bare når R er lavere alkanoyl omsettes en forbindelse med formel I med (C2H5)3PAUS-. where R is triphenylmethyl, lower alkanoyl or Ag where n is 1 or 2, X is chlorine, bromine or iodine or, only when R is lower alkanoyl a compound of formula I is reacted with (C2H5)3PAUS-.
Ved fremgangsmåten ifølge oppfinnelsen reagerer thioeteren eller thioesteren meget lett med det tertiære fosfingull-reagens (II). Som regel forløper reaksjonen ved ca. romtemperatur,' men temperaturer opp til reaksjonsblandingens kokepunkt kan anvendes. Et foretrukket temperaturintervall er fra 25 til 75°C. Reaksjonstiden er inntil reaksjonen er avsluttet men kan ligge fra 1/2 time opp til flere dager av-hengig av reaksjonens temperatur og reagensenes reaksjons-dyktighet. De tertiære fosfingullhalogenider er også mere reaksjonsdyktige enn sulfidene og er ikke så lett tilgjenge-lige som bis-tertiære fosfingullhalogenidene. In the method according to the invention, the thioether or thioester reacts very easily with the tertiary phosphine gold reagent (II). As a rule, the reaction proceeds at approx. room temperature,' but temperatures up to the boiling point of the reaction mixture can be used. A preferred temperature range is from 25 to 75°C. The reaction time is until the reaction is finished, but can be from 1/2 hour up to several days depending on the temperature of the reaction and the reaction ability of the reagents. The tertiary phosphine gold halides are also more reactive than the sulphides and are not as readily available as the bi-tertiary phosphine gold halides.
Generelt kan ethvert inert organisk oppløsningsmiddel hvori reaksjonsdeltakerne er oppløselige anvendes, som et al-minnelig halogenert hydrokarbonoppløsningsmiddél som kloroform, tetraklorkarbon, etylentetraklorid eller metylenklorid, et benzenoidt oppløsningsmiddel som benzen, toluen eller xylen, dimetylformamid, dimetylacetamid, eteriske opp-løsningsmidler som dietyleter eller dioxan, etylacetat, etylkarbonat, dimetylsulfoksyd, lavere alkanoler som metanol, etanol eller isopropanol. De lavere klorhydrokarboner In general, any inert organic solvent in which the reactants are soluble can be used, such as a general halogenated hydrocarbon solvent such as chloroform, carbon tetrachloride, ethylene tetrachloride or methylene chloride, a benzenoid solvent such as benzene, toluene or xylene, dimethylformamide, dimethylacetamide, ethereal solvents such as diethyl ether or dioxane , ethyl acetate, ethyl carbonate, dimethyl sulphoxide, lower alkanols such as methanol, ethanol or isopropanol. The lower chlorohydrocarbons
især metylenklorid foretrekkes. especially methylene chloride is preferred.
Reaksjonsproduktet auranofin isoleres på standardmåter, f.eks. ved avdamping av oppløsningsmidlet i våkum hvis nødvendig for dannelse av rå auranofin, som så renses ved kromatografi eller fraksjonert krystallisasjon. Utgangsmaterialene er enten kjent eller fremstilles ved reaksjoner som er beskrevet i de følgende eksempler. Alle temperaturer er °C. The reaction product auranofin is isolated in standard ways, e.g. by evaporating the solvent in vacuo if necessary to form crude auranofin, which is then purified by chromatography or fractional crystallization. The starting materials are either known or produced by reactions described in the following examples. All temperatures are °C.
Eksempel 1 Example 1
2, 3, 4, 6- tetra- O- acetyl- l- S- trityl- l- thio- B- D- glykopyranose 2, 3, 4, 6- tetra- O- acetyl- l- S- trityl- l- thio- B- D- glycopyranose
En pyridinoppløsning (100 ml) av 35 g (0,096 mol) 2,3,4,6-tetra-O-acetyl-l-thio-B-D-glykopyranose [Methods in Carbohy-drate Chemistry, bind 2, side 436 (1967)] og 28 g (0,10 mol) trifenylmetylklorid ble omrørt ved romtemperatur i 12 timer. Oppløsningen ble så filtrert og pyridinet fjernet ved redusert trykk. Resten ble oppløst i kloroform (350 ml), vasket med vann (5 x 100 ml) og kloroformoppløsningen tørket (magnesiumsulfat). Oppløsningsmidlet ble fjernet ved redusert trykk, A pyridine solution (100 ml) of 35 g (0.096 mol) of 2,3,4,6-tetra-O-acetyl-l-thio-B-D-glycopyranose [Methods in Carbohydrate Chemistry, vol. 2, page 436 (1967) ] and 28 g (0.10 mol) of triphenylmethyl chloride were stirred at room temperature for 12 hours. The solution was then filtered and the pyridine removed under reduced pressure. The residue was dissolved in chloroform (350 mL), washed with water (5 x 100 mL) and the chloroform solution dried (magnesium sulfate). The solvent was removed under reduced pressure,
og den gjenværende olje ble oppløst i metanol og avkjølt under dannelse av 17 g (29%) krystallinsk 2,3,4,6-tetra-O-acetyl-l-S-trityl-l-thio-3-D-glykopyranose, smeltepunkt 177 - 179°C, [a]^<5> (i% metanol) = -37,8°. and the remaining oil was dissolved in methanol and cooled to give 17 g (29%) of crystalline 2,3,4,6-tetra-O-acetyl-1-S-trityl-1-thio-3-D-glycopyranose, mp 177 - 179°C, [α]^<5> (in% methanol) = -37.8°.
En kloroformoppløsning (50 ml) av 3,0 g (4,9 mmol) 2,3,4,6-tetra-O-acetyl-l-S-trityl-l-thio-B-D-glykopyranose og 1,95 g (4,9 mmol) brom (trietylfosfin)gull (I) [Aust. J. Chem. 19, A chloroform solution (50 mL) of 3.0 g (4.9 mmol) of 2,3,4,6-tetra-O-acetyl-l-S-trityl-l-thio-B-D-glycopyranose and 1.95 g (4, 9 mmol) bromo(triethylphosphine)gold (I) [Aust. J. Chem. 19,
539 (1966)] ble omrørt ved romtemperatur i 48 timer og deretter tilbakekjølt 48 timer. Oppløsningsmidlet ble fjernet ved redusert trykk og resten underkastet søylekromatografi (silicagel/5% eter-kloroform). Krystallisasjon av det fremkomne rå produkt av metanol-vann ga auranofin som hvite krystaller, smeltepunkt 109 - 113°C [a]^5(l% metanol) = -55,7°. 539 (1966)] was stirred at room temperature for 48 hours and then cooled for 48 hours. The solvent was removed under reduced pressure and the residue subjected to column chromatography (silica gel/5% ether-chloroform). Crystallization of the resulting crude product from methanol-water gave auranofin as white crystals, melting point 109 - 113°C [a]^5(1% methanol) = -55.7°.
Ved å anvende støkiometriske mengder p-metoksybenzylklorid, benzylklorid, o,p-dimetoksybenzylklorid eller p-brombenzhydryl-bromid i stedet for trifenylmetyl(trityl) klorid i ovenstående reaksjoner fås auranofin. By using stoichiometric amounts of p-methoxybenzyl chloride, benzyl chloride, o,p-dimethoxybenzyl chloride or p-bromobenzhydryl bromide instead of triphenylmethyl (trityl) chloride in the above reactions, auranofin is obtained.
Eksempel 2 Example 2
2, 3, 4, 6- tetra- O- acetyl- l- S- trityl- l- thio- B- D- glykopyranose 2, 3, 4, 6- tetra- O- acetyl- l- S- trityl- l- thio- B- D- glycopyranose
En pyridinoppløsning (100 ml) av 35 g (0,096 mol) 2,3,4,6-tetra-O-acetyl-l-thio-B-D-glykopyranose [Methods in Carbohyd-rate Chemistry, bind 2, 436 (1963)] og 28 g (0,10 mol) trifenylmetylklorid ble omrørt ved romtemperatur i 12 timer. Opp-løsningen ble filtrert og pyridinet fjernet ved redusert trykk. Resten ble oppløst i kloroform (350 ml) vasket med vann (5 x 100 ml) og kloroformoppløsningen tørket over magnesiumsulfat. Oppløsningsmidlet ble fjernet ved redusert trykk og resten oppløst i metanol og avkjølt underdannelse av 17 g (29%) krystallinsk 2,3,4,6-tetra-O-acetyl-D-S-trityl-l-thio-Ø-D-glykopyranose, smeltepunkt 177 - 179°C, [a]^<5> (1% metanol) = -37,8°. A pyridine solution (100 ml) of 35 g (0.096 mole) of 2,3,4,6-tetra-O-acetyl-l-thio-B-D-glycopyranose [Methods in Carbohyd-rate Chemistry, Vol. 2, 436 (1963)] and 28 g (0.10 mol) of triphenylmethyl chloride was stirred at room temperature for 12 hours. The solution was filtered and the pyridine removed under reduced pressure. The residue was dissolved in chloroform (350 ml), washed with water (5 x 100 ml) and the chloroform solution dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue dissolved in methanol and cooled to give 17 g (29%) of crystalline 2,3,4,6-tetra-O-acetyl-D-S-trityl-1-thio-Ø-D-glycopyranose, melting point 177 - 179°C, [a]^<5> (1% methanol) = -37.8°.
En metanoloppløsning (30 ml) av 0,84 g (4,9 mmol) sølvnitrat og 3,0 g (4,9 mmol) 2,3,4,6-tetra-O-acetyl-l-S-trityl-l-thio-Ø-D-glykopyranose ble omrørt ved 35°C i 30 minutter. Oppløs-ningen ble så fortynnet til 100 ml med eter og avkjølt til -20°C natten over. Det fremkomne bunnfall ble fjernet ved filtrering, vasket med eter og tørket underdannelse av 1,94 g (83%) 2,3,4,6-tetra-O-acetyl-l-S-sølv-l-thio-B-D-glykopyranose, smeltepunkt 123 - 128°C. A methanol solution (30 mL) of 0.84 g (4.9 mmol) silver nitrate and 3.0 g (4.9 mmol) 2,3,4,6-tetra-O-acetyl-1-S-trityl-1-thio -Ø-D-glycopyranose was stirred at 35°C for 30 minutes. The solution was then diluted to 100 ml with ether and cooled to -20°C overnight. The resulting precipitate was removed by filtration, washed with ether and dried to yield 1.94 g (83%) of 2,3,4,6-tetra-O-acetyl-l-S-silver-l-thio-B-D-glycopyranose, m.p. 123 - 128°C.
En metanoloppløsning (35 ml) av 1,94 g (4,1 mmol) 2,3,4,6-tetra-O-acetyl-l-S-sølv-l-thio-B-D-glykopyranose og 1,44 (4,1 mmol) klor (trietylfosfin)gull (I) ble omrørt ved romtemperatur i 1 time. Oppløsningen ble filtrert og oppløsningsmidlet fjernet ved redusert trykk. Kromatografi av resten (silikagel/ kloroform) etterfulgt av krystallisasjon av metanol-vann ga auranofin, smeltepunkt 108 - 110°C, [a]^<5> (1% metanol) = -55,8°. A methanol solution (35 mL) of 1.94 g (4.1 mmol) of 2,3,4,6-tetra-O-acetyl-l-S-silver-l-thio-B-D-glycopyranose and 1.44 (4.1 mmol) chloro(triethylphosphine)gold (I) was stirred at room temperature for 1 hour. The solution was filtered and the solvent removed under reduced pressure. Chromatography of the residue (silica gel/chloroform) followed by crystallization from methanol-water gave auranofin, mp 108 - 110°C, [α]^<5> (1% methanol) = -55.8°.
Eksempel 3 Example 3
En kloroformoppløsning (25 ml) av 0,61 g (1,5 mmol) 2,3,4,6-tetra-O-acetyl-l-S-acetyl-l-thio-B-D-glykopyranose oa l,o g (.1,5 mmol) bis (trietylfosfingull) sulfid ble oppvarmet under tilbakeløp natten over og oppløsningsmidlet fjernet ved redusert trykk. Kromatografi av resten (silikagel, benzen-kloroform 0 til 100%) gir en gul olje med kloroformeluatet. Preparativ tyntlagskromatografi (silikagel, eter-2% aceton) etterfulgt av krystallisasjon av metanol-vann gir auranofin, smeltepunkt 110 - 111°C. A chloroform solution (25 ml) of 0.61 g (1.5 mmol) of 2,3,4,6-tetra-O-acetyl-l-S-acetyl-l-thio-B-D-glycopyranose oa l.o g (.1, 5 mmol) bis(triethylphosphine gold) sulfide was heated under reflux overnight and the solvent removed under reduced pressure. Chromatography of the residue (silica gel, benzene-chloroform 0 to 100%) gives a yellow oil with the chloroform eluate. Preparative thin layer chromatography (silica gel, ether-2% acetone) followed by crystallization from methanol-water gives auranofin, melting point 110 - 111°C.
Eksempel 4 Example 4
En kloroformoppløsning (25 ml) av 1,0 g (2,5 mmol) pentaacetyl-thioglykose og 1,15 g (2,5 mmol) bis(trietylfosfin)gullklorid ble omrørt ved romtemperatur i 72 timer og oppløsningsmidlet fjernet ved redusert trykk. Kromatografi av resten (silicagel, benzen-kloroform 0 til 100%) gir en olje, som ble renset ytter-ligere ved preparativ tyntlagskromatografi (silikagel, eter-2% aceton). Krystallisasjon av metanol-vann gir auranofin, smeltepunkt 98-101°C. A chloroform solution (25 mL) of 1.0 g (2.5 mmol) pentaacetylthioglycose and 1.15 g (2.5 mmol) bis(triethylphosphine)gold chloride was stirred at room temperature for 72 h and the solvent removed under reduced pressure. Chromatography of the residue (silica gel, benzene-chloroform 0 to 100%) gives an oil, which was further purified by preparative thin layer chromatography (silica gel, ether-2% acetone). Crystallization of methanol-water gives auranofin, melting point 98-101°C.
Claims (2)
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US05/811,670 US4122254A (en) | 1977-06-30 | 1977-06-30 | Process for preparing auranofin |
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NO782242L NO782242L (en) | 1979-01-03 |
NO145308B true NO145308B (en) | 1981-11-16 |
NO145308C NO145308C (en) | 1982-02-24 |
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US (1) | US4122254A (en) |
AT (1) | AT359088B (en) |
CH (1) | CH636103A5 (en) |
DK (1) | DK150520C (en) |
FI (1) | FI64167C (en) |
FR (1) | FR2396023A1 (en) |
GB (1) | GB1593355A (en) |
IE (1) | IE47109B1 (en) |
IL (1) | IL55023A (en) |
IT (1) | IT1158862B (en) |
NO (1) | NO145308C (en) |
PT (1) | PT68211A (en) |
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NZ228367A (en) * | 1988-03-23 | 1992-02-25 | Smithkline Beecham Corp | Topical composition containing a gold compound for treating inflammatory conditions |
US5527779A (en) * | 1988-03-23 | 1996-06-18 | Top Gold Pty Limited | Topically applied gold organic complex |
US5170437A (en) * | 1990-10-17 | 1992-12-08 | Audio Teknology, Inc. | Audio signal energy level detection method and apparatus |
CN105418696B (en) * | 2014-09-10 | 2018-09-21 | 华中科技大学 | A kind of synthetic method of glycosyl mercaptan and Anranofin |
US20180020669A1 (en) | 2015-02-06 | 2018-01-25 | Auspherix Limited | Methods for the Inhibition and Dispersal of Biofilms |
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1977
- 1977-06-30 US US05/811,670 patent/US4122254A/en not_active Expired - Lifetime
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1978
- 1978-05-09 FR FR7813671A patent/FR2396023A1/en active Granted
- 1978-05-25 GB GB22831/78A patent/GB1593355A/en not_active Expired
- 1978-06-12 AT AT427578A patent/AT359088B/en not_active IP Right Cessation
- 1978-06-22 YU YU01479/78A patent/YU147978A/en unknown
- 1978-06-26 PT PT68211A patent/PT68211A/en unknown
- 1978-06-26 IT IT24982/78A patent/IT1158862B/en active
- 1978-06-26 DK DK286478A patent/DK150520C/en not_active IP Right Cessation
- 1978-06-26 FI FI782033A patent/FI64167C/en not_active IP Right Cessation
- 1978-06-27 IL IL55023A patent/IL55023A/en unknown
- 1978-06-28 IE IE1300/78A patent/IE47109B1/en not_active IP Right Cessation
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Publication number | Publication date |
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NO145308C (en) | 1982-02-24 |
AT359088B (en) | 1980-10-27 |
FR2396023B1 (en) | 1980-07-18 |
IE47109B1 (en) | 1983-12-28 |
CH636103A5 (en) | 1983-05-13 |
IE781300L (en) | 1978-12-30 |
IT1158862B (en) | 1987-02-25 |
DK286478A (en) | 1978-12-31 |
YU147978A (en) | 1982-10-31 |
IT7824982A0 (en) | 1978-06-26 |
NO782242L (en) | 1979-01-03 |
FI64167C (en) | 1983-10-10 |
FR2396023A1 (en) | 1979-01-26 |
FI64167B (en) | 1983-06-30 |
DK150520B (en) | 1987-03-16 |
ATA427578A (en) | 1980-03-15 |
US4122254A (en) | 1978-10-24 |
PT68211A (en) | 1978-07-01 |
GB1593355A (en) | 1981-07-15 |
FI782033A (en) | 1978-12-31 |
IL55023A (en) | 1981-09-13 |
IL55023A0 (en) | 1978-08-31 |
DK150520C (en) | 1988-01-11 |
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